DiagnosisClinical DiagnosisL1 syndrome involves a phenotypic spectrum ranging from severe to mild. Before the availability of molecular genetic testing, several of the phenotypes were thought to be distinct entities. These phenotypes, which are useful in facilitating clinical diagnosis and providing prognosis, have traditionally comprised the following:X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS). Signs present in affected males: Severe hydrocephalus, often of prenatal onset. The clinical criteria for hydrocephalus: Increased intraventricular fluid volume evidenced by an increased occipital-frontal circumference and imaging findings such as increased ventricular size, loss of cerebral sulci, and transependymal resorption of cerebrospinal fluid Increased intraventricular pressure based on: (1) specific clinical signs and symptoms depending on age, such as progressive increase of OFC (occipital frontal circumference), headache, nausea and vomiting, irritability; and/or (2) ultrasound and/or brain imaging; or (3) intracranial pressure measurements with ventricular catheter or lumbar puncture [Schrander-Stumpel & Fryns 1998] Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicus longis and/or brevis muscles (>50% of males) [Schrander-Stumpel & Fryns 1998] Spasticity evidenced by brisk tendon reflexes and extensor plantar responses Severe intellectual disability MASA syndrome (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia [shuffling gait], adducted thumbs) [Bianchine & Lewis 1974, Schrander-Stumpel et al 1990]. Findings in affected males: Mild to moderate intellectual disability Delayed onset of speech Hypotonia progressing to spasticity Adducted (clasped) thumbs caused by a developmental defect of the extensor pollicis longis and/or brevis muscles Variable dilatation of the third ventricle SPG1 (X-linked complicated hereditary spastic paraplegia type 1). Findings in affected males: Spastic paraplegia Mild to moderate intellectual disability Normal MRI of the brain X-linked complicated corpus callosum agenesis [Willems et al 1987, Boyd et al 1993, Schrander-Stumpel 1995, Yamasaki et al 1995]. Findings in affected males: Variable spastic paraplegia Mild to moderate intellectual disability Corpus callosum dysplasia, hypoplasia, or aplasia TestingNeuropathology and neuroimaging reveal hydrocephalus with or without stenosis of the aqueduct of Sylvius in combination with corpus callosum agenesis/hypogenesis and/or cerebellar hypoplasia, small brain stem, and agenesis of the pyramids (corticospinal tracts) [Willems et al 1987, Yamasaki et al 1995]. Bilateral absence of the pyramids detected by MRI or autopsy is an almost pathognomonic finding [Chow et al 1985, Schrander-Stumpel et al 2000]. Aqueductal stenosis is not a constant feature of L1 syndrome [Landrieu et al 1979, Varadi et al 1987, Yamasaki et al 1995]. Molecular Genetic TestingGene. L1CAM is the only gene associated with L1 syndrome. Clinical testing Sequence analysis. Mutation detection frequencies using sequence analysis have not been reported in the literature. Sequence analysis may have a slightly greater sensitivity than mutation scanning, and thus a higher detection frequency. Mutation scanning. Vos et al [2010] used denaturing gradient gel electrophoresis (DGGE) to identify mutations in L1CAM. (See Table 2 for mutation detection frequencies related to clinical findings and family history.) Duplication/deletion analysis. The frequency of deletions and duplications is low: to date six large deletions or duplications including one deletion of the entire gene have been described [Knops et al 2008].One deletion of the promoter region and exon 1 [Tegay et al 2007] One 2-kb deletion at the distal part of the gene: c.3543_?del2kb [Vits et al 1994] One deletion of exons 2-5 and part of exon 6 [Panayi et al 2005]One duplication of 1.3 kb: c.3543_?dup1.3kb [Van Camp et al 1993]One duplication of exons 2-10 [Vos et al 2010] Note: In males, deletions are inferred by absence of a PCR product in mutation scanning and sequence analysis; duplication analysis is necessary for confirmation (see Table 1 footnote 5). Table 1. Summary of Molecular Genetic Testing Used in L1 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityAffected Males Carrier Females L1CAMSequence analysisSequence variants 2 100%100%ClinicalPartial- and whole-gene deletions0% 3Deletion / duplication analysis 4Partial- and whole-gene deletionsSee footnote 5Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Sequence analysis cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Deletion analysis can be used to confirm a putative exonic/whole-gene deletion in males after failure of DNA to amplify by PCR in the sequence analysis.Table 2. Detection of L1CAM Mutations in Probands by Mutation ScanningView in own windowFamily HistoryMutation Detection Frequency by Number of Clinical Findings 1≥3 FindingsNegative9%50%≥2 affected family members32%85%Adapted from Vos et al [2010] 1. Age-independent clinical characteristics: hydrocephalus, aqueduct stenosis, adducted thumbs, agenesis/dysgenesis of the corpus callosumInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband, L1CAM molecular genetic testing is performed: 1.Initially sequence analysis2.Followed by deletion/duplication analysis as neededCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may manifest clinical findings related to the disorder. The features are usually minor symptoms of the clinical spectrum; however, severe hydrocephalus has been reported in a female carrier [Kaepernick et al 1994, Vos et al 2010]. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations of L1CAM.}

Natural HistoryAffected males. In L1 syndrome, the major features are hydrocephalus, intellectual disability, spasticity of the legs, and adducted thumbs. Hydrocephalus may be present prenatally and result in stillbirth or death in early infancy. Males with hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) are born with severe hydrocephalus and adducted thumbs. Seizures may occur. In less severely affected males, hydrocephalus may be subclinically present and documented only because of developmental delay. Mild-to-moderate ventricular enlargement is compatible with long survival. In HSAS, intellectual disability is usually severe and is independent of shunting procedures in individuals with severe hydrocephalus. In MASA syndrome, intellectual disability ranges from mild (IQ: 50-70) to moderate (IQ: 30-50). The degree of intellectual impairment does not necessarily correlate with head size or severity of hydrocephalus; males with severe intellectual disability and a normal head circumference have been reported.Boys initially exhibit hypotonia of the legs, which evolves into spasticity during the first years of life. In adult males, the spasticity tends to be somewhat progressive, although this finding has not been documented in a large group. Spasticity usually results in atrophy of the muscles of the legs and contractures that together cause the shuffling gait.All phenotypes can be observed in affected individuals in the same family. Other findings of unknown significance in individuals with L1CAM mutations and L1 syndrome. At least 13 individuals with an L1CAM mutation and a combination of L1 syndrome and Hirschsprung disease (HSCR) have been reported [Okamoto et al 1997, Vits et al 1998, Parisi et al 2002, Okamoto et al 2004, Basel-Vanagaite et al 2006, Tegay et al 2007, Nakakimura et al 2008, Jackson et al 2009, Griseri et al 2009]. HSCR is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. It has been suggested that failure of migration of the neural crest cells underlies aganglionosis. Parisi et al [2002] hypothesized that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause aganglionosis. An L1CAM mutation alone does not result in HSCR. Another report presents an association between X-linked hydrocephalus and a specific form of congenital idiopathic intestinal pseudo-obstruction (CIIP) in an infant [Bott et al 2004] in whom an L1CAM mutation had been detected.Carrier females. Females may manifest minor features such as adducted thumbs and/or subnormal intelligence. Rarely do females manifest the complete L1 syndrome phenotype. Severe hydrocephalus has been reported in a female carrier [Kaepernick et al 1994, Vos et al 2010].

Genotype-Phenotype CorrelationsIn their review, Weller & Gärtner [2001] noted that missense mutations in extracellular domains or mutations in cytoplasmic regions cause milder phenotypes than those resulting from truncation in extracellular domains or from nondetectable L1 protein.Missense mutations that affect 'key amino acid residues' are most likely to result in a severe phenotype. Key amino acid residues are those crucial for the structure of the immunoglobulin or fibronectin type III-like domains of the L1 protein [Bateman et al 1996].The above generalizations about genotype-phenotype correlations notwithstanding, clinical findings in L1 syndrome can range from mild to severe even in the same family, indicating that other factors must influence the clinical presentation [Finckh et al 2000].

Differential DiagnosisThe differential diagnosis of males with developmental delay or intellectual disability and early hypotonia evolving into spastic paraplegia during childhood, with or without adducted thumbs, includes many conditions. In newborns with hydrocephalus, other causes of hydrocephalus should be excluded [Schrander-Stumpel & Fryns 1998]. Hydrocephalus is often divided into nonsyndromic forms and syndromic forms: Nonsyndromic congenital hydrocephalus As part of a neural tube defect Isolated hydrocephalus: Congenital aqueductal stenosis Autosomal recessive hydrocephalus As part of a CNS malformation: Arnold-Chiari malformation Dandy-Walker malformation Holoprosencephaly Hydranencephaly Vein of Galen malformation Midline hyperplasia with malformation of the fornical system Congenital cyst Other midline abnormalities Congenital communicating hydrocephalus secondary to hemorrhage Syndromic congenital hydrocephalus Cytogenetic abnormalities: Trisomy 13 Trisomy 18 Trisomy 9 and 9p (mosaic) Triploidy Others Mendelian (single-gene) conditions: Walker-Warburg syndrome (see Congenital Muscular Dystrophy Overview) Hydrolethalus syndrome Meckel-Gruber syndrome Smith-Lemli-Opitz syndrome Mucopolysaccharidosis type I Mucopolysaccharidosis type II (Hunter syndrome) Fanconi anemia syndrome (VACTERL with hydrocephalus) FGFR-related craniosynostosis Crouzon syndrome Apert syndrome Associations and disruptions: Oculoauricoluvertebral spectrum Hydranencephaly Porencephaly VACTERL association PLP1-related disorders (including SPG2). The PLP1-related disorders of central nervous system myelin formation caused by mutations in PLP1 include the spectrum of phenotypes ranging from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. SPG2 can be “complicated” or “uncomplicated” (pure) spastic paraparesis. Complicated SPG2 often includes autonomic dysfunction (e.g., spastic urinary bladder), ataxia, and nystagmus; pure SPG2 does not have other significant CNS signs; however, autonomic dysfunction including spastic urinary bladder may also occur. A wide range of phenotypes can be observed in members of the same family. Clinical diagnosis depends on the typical neurologic findings, X-linked recessive inheritance pattern, and, usually, diffusely abnormal myelin on MRI. Because of clinical overlap between the SPG1 phenotype of L1 syndrome and the SPG2 phenotype of the PLP1-related disorders, it may be difficult to make the diagnosis of the L1 syndrome on clinical grounds alone especially when hydrocephalus is absent in affected males. See also Hereditary Spastic Paraplegia Overview.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).HSASX-linked corpus callosum agenesisSPG1MASA syndrome

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with L1 Syndrome, the following evaluations are recommended:Head imaging study Complete neurologic evaluation Developmental evaluation Treatment of ManifestationsOptimal management involves a multidisciplinary team with expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics. Hydrocephalus. Surgical treatment should be performed as needed. Shunting of the cerebrospinal fluid (CSF) is indicated to reduce intracranial pressure. Of note, prenatal shunting procedures offer no advantage [Pinckert & Golbus 1988]. Intellectual disability. Developmental progress should be monitored and stimulated. Developmental outcome is variable and individual counseling important. Adducted thumbs. Surgical intervention is not indicated. In some milder cases, tendon transfer may improve thumb function. A splint helps reduce the degree of adduction is some cases. Spastic paraplegia. Neurologic features should be monitored. Follow-up and treatment is nonspecific; general guidelines can be followed. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. L1 Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDL1CAMXq28Neural cell adhesion molecule L1HSP mutation database
L1CAM Mutation Web Page
L1CAM @ LOVDL1CAMData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for L1 Syndrome (View All in OMIM) View in own window 303350MASA SYNDROME 307000HYDROCEPHALUS DUE TO CONGENITAL STENOSIS OF AQUEDUCT OF SYLVIUS; HSAS 308840L1 CELL ADHESION MOLECULE; L1CAMNormal allelic variants. L1CAM consists of 29 exons, 28 of which are coding [Kallunki et al 1997]. The non-coding exon (exon 1A) of 125 bp is about 10 kb upstream of exon 1, the first coding exon. The mRNA has been shown to be alternatively spliced. The neuronal form (NM_000425.3 includes a neuron-specific exon in the 3' region and encodes the full-length isoform) of L1CAM contains exon 2 and exon 27, while they are excluded from the non-neuronal mRNA. Missense mutations that are non-pathogenic polymorphisms and mutations of unknown pathogenic relevance have also been reported [Finckh et al 2000, Weller & Gärtner 2001]. Pathologic allelic variants. L1CAM mutations, the majority of which appear to be private, are scattered throughout the gene. All types of disease-causing mutations are found: nonsense, frameshift, splice site, and missense mutations. The nonsense and frameshift mutations lead to truncation of the L1 protein. To date, 247 different mutations in about 300 families with L1 syndrome have been reported (www.l1cammutationdatabase.info). See Vos & Hofstra [2010].Normal gene product. The protein consists of 1257 amino acids with a molecular weight of 200 kd (including carbohydrates). The L1 cell adhesion molecule (L1CAM) is a cell surface (transmembrane) glycoprotein. It belongs to the large class of immunoglobulin superfamily proteins with an extracellular part consisting of six immunoglobulin-like (Ig-like) domains and five fibronectin type III-like (FNIII) domains, a single-pass transmembrane domain, and a short cytoplasmic domain [Weller & Gärtner 2001]. L1 is expressed on neurons, both in the central nervous system and the peripheral nervous system. On differentiated neurons, L1 is found at regions of contact between neighboring axons and on the growth cones. The L1 protein mediates cell-cell adhesion through homophilic and heterophilic interactions with other L1 protein molecules and with various ligands. L1 ligand binding is linked to intracellular signaling pathways and the L1 protein is involved in modification of cytoskeleton interactions [Kenwrick et al 2000].Abnormal gene product. Truncated proteins caused by a nonsense mutation in the extracellular part of the protein lack the transmembrane domain and thus contact between neurons is impaired. The truncated proteins are either secreted into the extracellular space or degraded quickly [Kamiguchi & Lemmon 1997, Brümmendorf et al 1998]. Truncating or missense mutations in the cytoplasmic domain act on a highly conserved domain that contains binding and phosphorylation sites. Abnormal proteins resulting from missense mutations in the extracellular domain may lose function by altered folding or trafficking or by altered ligand binding [Kenwrick et al 2000, De Angelis et al 2002, Rünker et al 2003].